Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2009-2018 ◽  
Author(s):  
Joseph L. Roberts ◽  
Andrea Lengi ◽  
Stephanie M. Brown ◽  
Min Chen ◽  
Yong-Jie Zhou ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Janus Kinase ◽  
Cell Functions ◽  
Janus Kinase 3

Abstract We found 10 individuals from 7 unrelated families among 170 severe combined immunodeficiency (SCID) patients who exhibited 9 different Janus kinase 3 (JAK3) mutations. These included 3 missense and 2 nonsense mutations, 1 insertion, and 3 deletions. With the exception of 1 individual with persistence of transplacentally transferred maternal lymphocytes, all infants presented with a T–B+NK– phenotype. The patient mutations all resulted in abnormal B-cell Janus kinase 3 (JAK3)–dependent interleukin-2 (IL-2)–induced signal transducer and activator of transcription-5 (STAT5) phosphorylation. Additional analyses of mutations permitting protein expression revealed the N-terminal JH7 (del58A) and JH6 (D169E) domain mutations each inhibited receptor binding and catalytic activity, whereas the G589S JH2 mutation abrogated kinase activity but did not affect γc association. Nine of the 10 patients are currently alive from between 4 years and 18 years following stem cell transplantation, with all exhibiting normal T-cell function. Reconstitution of antibody function was noted in only 3 patients. Natural killer (NK) function was severely depressed at presentation in the 4 patients studied, whereas after transplantation the only individuals with normal NK lytic activity were patients 1 and 5. Hence, bone marrow transplantation is an effective means for reconstitution of T-cell immunity in this defect but is less successful for restoration of B-cell and NK cell functions.

scholarly journals Early Reconstitution of Antibody Secreting Cells after Allogeneic Stem Cell Transplantation

2022 ◽  
Vol 11 (1) ◽  
pp. 270
Author(s):  
Martina Hinterleitner ◽  
Clemens Hinterleitner ◽  
Elke Malenke ◽  
Birgit Federmann ◽  
Ursula Holzer ◽  
...  
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Antibody Secreting Cells

Immune cell reconstitution after stem cell transplantation is allocated over several stages. Whereas cells mediating innate immunity recover rapidly, adaptive immune cells, including T and B cells, recover slowly over several months. In this study we investigated kinetics and reconstitution of de novo B cell formation in patients receiving CD3 and CD19 depleted haploidentical stem cell transplantation with additional in vivo T cell depletion with monoclonal anti-CD3 antibody. This model enables a detailed in vivo evaluation of hierarchy and attribution of defined lymphocyte populations without skewing by mTOR- or NFAT-inhibitors. As expected CD3+ T cells and their subsets had delayed reconstitution (<100 cells/μL at day +90). Well defined CD19+ B lymphocytes of naïve and memory phenotype were detected at day +60. Remarkably, we observed a very early reconstitution of antibody-secreting cells (ASC) at day +14. These ASC carried the HLA-haplotype of the donor and secreted the isotypes IgM and IgA more prevalent than IgG. They correlated with a population of CD19− CD27− CD38low/+ CD138− cells. Of note, reconstitution of this ASC occurred without detectable circulating T cells and before increase of BAFF or other B cell stimulating factors. In summary, we describe a rapid reconstitution of peripheral blood ASC after CD3 and CD19 depleted haploidentical stem cell transplantation, far preceding detection of naïve and memory type B cells. Incidence before T cell reconstitution and spontaneous secretion of immunoglobulins allocate these early ASC to innate immunity, eventually maintaining natural antibody levels.

Phase I Dose-Escalation Trial of BI 2536, a Polo-Like Kinase 1 Inhibitor, in Relapsed and Refractory Non-Hodgkin’s Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 233-233 ◽  
Author(s):  
Julie M. Vose ◽  
Anas Young ◽  
Jonathan W. Friedberg ◽  
Edmund K. Waller ◽  
Bruce D. Cheson ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Antitumor Activity ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
B Cell ◽  
Cell Transplantation ◽  
Safety Profile ◽  
Cell Lymphoma ◽  
Bi 2536

Abstract Background: BI 2536 is a highly potent, selective inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression. BI 2536 has demonstrated favorable tolerability and antitumor activity in Phase I trials in patients with solid tumors. Antitumor activity of BI 2536 was also shown in preclinical non-Hodgkin’s lymphoma (NHL) models. We determined the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and efficacy of BI 2536 given as an intravenous infusion once every 3 weeks in patients with relapsed or refractory aggressive NHL of T- or B-cell origin. Methods: Sequential cohorts of 3–6 patients with relapsed or refractory aggressive NHL received 1-hour infusions of BI 2536 following a toxicity-guided Phase 1 doseescalation design. Patients relapsed after peripheral stem cell transplantation and transplantation-naive patients were entered into different strata and the respective MTD determined independently. A single administration was given every 21 days. Patients with clinical benefit were eligible for further treatment courses after recovery from toxicity after a 3-week observation period. A total of 41 patients were entered into the trial: 24 patients in the transplant-naive (non-tr) stratum; and 17 patients in the transplant-failure (tr) stratum. Patients were treated at dose levels from 50 to 200 mg. Results: The safety profile was similar in both strata with the MTD determined independently at 175 mg for both non-tr and tr patients. Neutropenia (tot: 33%; CTCAE Grade (gr)3/4: 21%), anemia (tot: 29%; gr3: 4%), thrombocytopenia (tot: 29%; gr3/4: 17%), fatigue (tot: 25%; gr3: 4%) and nausea (tot=gr1/2: 25%) were the most frequent adverse events in non-tr; and thrombocytopenia (tot: 59%; gr3/4: 41%), anemia (tot=gr1/2: 41%), fatigue (tot=gr1/2: 41%) and neutropenia (tot: 41%; gr3/4: 21%) were most frequent in tr patients. Dose-limiting toxicities (DLTs) consisted of reversible thrombocytopenia (six patients) and neutropenia (three patients). No relevant non-specific toxicity was observed. Pharmacokinetic analysis showed dose proportionality of Cmax and AUC0–∞ with a high clearance (~1,400 mL/min) and a high volume of distribution (&gt;1,000 L). Patients were treated for up to 6 courses without evidence of cumulative toxicity. Three complete responses (CRs) and one partial response were observed. Stable disease as best response was noted in three (18%) of tr patients and nine (38%) of non-tr patients. All responders had relapsed after prior peripheral stem cell transplants and were treated at doses of 150–200 mg. Three of the four responders had a peripheral T-cell lymphoma (PTCL) NHL; one CR was observed in a patient with diffuse large B-cell lymphoma. The overall response rate (ORR) in the tr stratum was 23.5%; in the aggregate of both tr and non-tr, the ORR amounted to 9.7%. With three out of five patients responding, an ORR of 60% was observed in the T-cell subset. However, the responses were of short duration. Conclusion: BI 2536 has a favorable safety and PK profile in patients with NHL. Safety profile and PK properties are comparable to data obtained in solid tumor patient populations. Encouraging, albeit transient, anti-lymphoma efficacy was observed in patients suffering from PTCL after autologous stem-cell transplantation.

scholarly journals Transfer of influenza vaccine–primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trial

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 63-71 ◽  
Author(s):  
Edward A. Stadtmauer ◽  
Dan T. Vogl ◽  
Eline Luning Prak ◽  
Jean Boyer ◽  
Nicole A. Aqui ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Influenza Vaccine ◽  
B Cell ◽  
Cell Transplantation ◽  
Study Endpoint ◽  
Cell Product ◽  
Cell Immunity

Abstract Severe immune deficiency follows autologous stem cell transplantation for multiple myeloma and is associated with significant infectious morbidity. This study was designed to evaluate the utility of a pretransplantation vaccine and infusion of a primed autologous T-cell product in stimulating specific immunity to influenza. Twenty-one patients with multiple myeloma were enrolled from 2007 to 2009. Patients were randomly assigned to receive an influenza-primed autologous T-cell product or a nonspecifically primed autologous T-cell product. The study endpoint was the development of hemagglutination inhibition titers to the strain-specific serotypes in the influenza vaccine. Enzyme-linked immunospot assays were performed to confirm the development of influenza-specific B-cell and T-cell immunity. Patients who received the influenza-primed autologous T-cell product were significantly more likely to seroconvert in response to the influenza vaccine (P = .001). Seroconversion was accompanied by a significant B-cell response. No differences were observed in the global quantitative recovery of T-cell and B-cell subsets or in global T-cell and B-cell function. The provision of a primed autologous T-cell product significantly improved subsequent influenza vaccine responses. This trial was registered at www.clinicaltrials.gov as #NCT00499577.

scholarly journals Donor-Derived Second Generation of CD19 CAR-T Cell Therapy for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogenic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2179-2179 ◽  
Author(s):  
Rongli Zhang ◽  
Yi He ◽  
Donglin Yang ◽  
Ying Wang ◽  
Sizhou Feng ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Second Generation ◽  
Allogenic Stem Cell Transplantation ◽  
Car T Cell ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Background: Patients with B cell acute lymphoblastic leukemia (B-ALL) relapsed after allogenic hematopoietic stem cell transplantation have poor prognosis. Donor lymphocyte infusion (DLI) have shown limited success in the setting of relapse by a mere increase in median survival by 6 months and a significant risk of acute and chronic graft-versus-host disease (GVHD) and additional risk of marrow aplasia. The second generation chimeric antigen receptor-T cell (CAR-T) for CD19 is a promising treatment for relapsed and refractory B-ALL, but the effectiveness and safety of donor-derived second generation of CD19 CAR-T cell infusion for relapsed B-ALL after allogenic stem cell transplantation have not been determined. Methods: Between July 2017 and June 2018, 6 adult patients with B-ALL relapsed (2 patients were hematologic relapsed; 4 patients were minimal residual disease(MRD)-positive) after allogenic stem cell transplantation were enrolled, including 5 sibling-matched stem cell transplantation and 1 haploidentical transplantation . Donor's T cells were infected with lentivirus carrying CD19 CAR plasmid which containing CD19 scfv (HI-19 clone) and 4-1BB-CD3ζ signaling domains to generate CAR-T cells. Patients received FAC (fludarabine:25-30mg/m2/d*3, cyclophosphamide:350mg/m2/d*2, cytosine arabinoside:100mg/m2/d*4) pretreatment and then total (1.25-3.5)*106/kg donor-derived 4-1BB CAR-T cell were infused in consecutive 2 or 3 days . Results: All the patients achieved MRD negative remission and complete donor chimerism. Three patients experienced grade 2 cytokine release syndrome (CRS) and received 6-8mg/kg interleukin-6 receptor blocker (tocilizumab) treatment ; the other 3 just experienced grade 1 CRS. None of these patients needed glucocorticoid treatment. No patients developed acute or chronic graft-versus-host disease (GVHD). Now all the 6 patients are alive and show complete donor chimerism with MRD negative remission. The median follow-up time are 243.5days. Conclusion: Donor-derived second generation of CD19 CAR-T cell treatment for relapsed B-ALL after allogenic stem cell transplantation were effective and safe, which may be confirmed with more clinical studies. Key words: donor-derived CD19 CAR-T cell therapy, allogenic stem cell transplantation, B cell acute lymphoblastic leukemia, relapse Disclosures No relevant conflicts of interest to declare.

scholarly journals Effectiveness of T-Cell Replete Haploidentical Hematopoietic Stem Cell Transplantation for Refractory/Relapsed B Cell Acute Lymphoblastic Leukemia in Children and Adolescents

2021 ◽  
Vol 9 ◽  
Author(s):  
Hideki Sano ◽  
Kazuhiro Mochizuki ◽  
Shogo Kobayashi ◽  
Yoshihiro Ohara ◽  
Nobuhisa Takahashi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem

Background: The prognosis of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains dismal owing to acquired resistance to chemotherapeutic agents. This study aimed to evaluate the efficacy of T-cell replete HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) for pediatric refractory/relapsed BCP-ALL (RR-BCP-ALL).Methods: Nineteen pediatric patients with RR-BCP-ALL underwent TCR-haplo-HSCT between 2010 and 2019 at the Fukushima Medical University Hospital. The disease status at TCR-haplo-HSCT included complete remission (CR) in eight patients and non-CR with active disease in 11 patients. Total body irradiation-based, busulfan-based, and reduced-intensity conditioning regimens were employed in 11, 6, and 2 patients, respectively. Low-dose anti-thymocyte globulin (thymoglobulin, 2.5 mg/kg) was used in all patients. Graft-vs.-host disease (GVHD) prophylaxis was administered with tacrolimus, methotrexate, and prednisolone.Results: All patients received peripheral blood stem cells as the stem cell source. The HLA disparities in graft vs. host directions were 2/8 in one, 3/8 in five, and 4/8 in 13 patients. Among 18 patients who achieved primary engraftment, acute GVHD occurred in all 18 evaluable patients (grade II, 9; grade III, 8; grade IV, 1), and chronic GVHD was observed in 10 out of 15 evaluable patients. Three patients died because of transplant-related mortality. The 3-year overall survival (OS) and leukemia-free survival rates were 57.4 and 42.1%, respectively. Compared to patients older than 10 years in age (N = 10), those younger than 10 years in age (N = 9) showed an excellent OS rate (3-year OS rate: patients &lt; 10 years old, 100%; patients &gt; 10 years old, 20% [95% confidence interval, 3.1–47.5]; p = 0.002).Conclusions: We suggest that TCR haplo-HSCT with low-dose ATG conditioning has the potential to improve the transplantation outcomes in patients with RR-BCP.

Rapid Reconstitution of Human Antibody Secreting Cells After Haploidentical Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3682-3682
Author(s):  
Martina Steurer ◽  
Elke Malenke ◽  
Birgit Federmann ◽  
Lothar Kanz ◽  
Wolfgang Andreas Bethge ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Stem Cell ◽  
T Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Adaptive Immunity ◽  
Cell Transplantation ◽  
Innate And Adaptive Immunity ◽  
Antibody Secreting Cells

Abstract Abstract 3682 Poster Board III-618 Innate immunity including granulocytes, monocytes, and NK cells is reported to recover rapidly after allogeneic stem cell transplantation within weeks. In contrast, adaptive immunity, including T- and B-cells, has delayed recovery over months. In murine models innate type marginal zone and B1 B cells, established at fetal age and providing natural antibodies, are distinguished from adaptive B2 or follicular B cells. A crucial maturation and survival factor for adaptive murine B cells was shown to be TNF-family member BAFF (B cell-activating factor), while development of innate B1 B cells is BAFF independent. Kinetics in reconstitution of innate and adaptive immunity after ablation in adults may give insight into hierarchy and attribution to innate and adaptive immunity of defined lymphocyte populations. Reconstitution of lymphopoiesis after CD3 and CD19 depleted haploidentical stem cell transplantation was analyzed in 10 patients, which received monoclonal anti-CD3 antibody OKT3 as immunosuppressant only. This model may enable detailed in vivo evaluation of de novo B cell formation. Weekly samples before and after reduced-intensity conditioning were analyzed by flow cytometry for absolute numbers of T-cell, NK-, and B-cell subsets. Their origin of host or donor hematopoiesis was differentiated by HLA-FACS. Antibody secreting cells (ASC) were enumerated by ELISPOT. Plasma cytokine concentrations were determined by bead based arrays and ELISA. Complete reconstitution of allogeneic NK cells was found at day +21 after transplantation. CD4+ and CD8+ T-cells and their subsets had delayed reconstitution with less then 100 cells/μl at 3 months after transplantation. CD19+ B-lymphocytes of naïve and memory phenotype (>0,5% of all lymphocytes) were detected not before day +60. In contrast, complete reconstitution of antibody-secreting cells after a nadir (<0,05/μl) was observed at day +14. Absolute numbers of ASC were comparable to those of healthy controls (d+14: 72 ASC/μl vs. control: 12 ASC/μl). ASC secreting the isotypes IgM and IgA were more prevalent than IgG compared to controls (time increase: IgM 20; IgA 10; IgG 2,9). These ASC appear CD19low/neg, CD38+, and intracellular Ig+ in flow cytometry and carried donor HLA-haplotype. Reconstitution of ASC occurred without detectable circulating T-cells and before increase of BAFF concentrations were observed. In summary, the rapid and complete reconstitution of peripheral blood ASC after allogeneic transplantation, far proceeding detection of naïve and memory type B-cells, is a novel observation. Incidence before T-cell reconstitution and increase in BAFF concentrations indicates a T-cell and BAFF independent mechanism allocating these early ASC to innate immunity, potentially maintaining natural antibody levels. Disclosures: No relevant conflicts of interest to declare.

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